In his graduate work with Edward Herbert at the University of Oregon (1979-1986), Mark studied the neuroendocrine secretory protein, chromogranin A, using recombinant DNA techniques to obtain the primary structure. Interest in this protein’s role in secretion led him to Regis Kelly's lab at the University of California, San Francisco for postdoctoral studies (1987-1991), where he developed an in vitro reconstitution method with permeabilized cells to study regulated and constitutive secretory vesicle sorting in the trans-Golgi network. Mark then traveled to New Zealand in 1994 and became Senior Lecturer for the Department of Chemistry and Biochemistry at the Institute of Molecular Biosciences at Massey University in Palmerston North, New Zealand. Back in the USA, Mark became Associate Professor for the Division of Biological Sciences at the University of Montana in 2002. He joined CSFN in 2003 and became interested in neurotrophin signalling and has developed a permeabilized cell technique to isolate signalling endosomes containing neurotrophin receptors.   

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INTERESTS OF THE GRIMES LABORATORY

In mammals, neurons are selected during development by their ability to form and maintain functional connections. A nerve cell commits suicide (programmed cell death, or apoptosis) unless told to stay alive by its connecting partner, the axon’s target. The command to stay alive is in the form of polypeptide growth factors, neurotrophins such as nerve growth factor (NGF), secreted from the neuron’s target. Without this command, neurons constitutively initiate apoptosis. My research program is focused on the question: what is the precise nature of events that govern the point at which a nerve cell decides to die or not to die? My plan is to characterize the components and function of protein machines that transduce NGF’s signals by purifying organelles and large protein complexes containing NGF receptors and downstream signalling proteins, elucidating their function using in vitro reconstitution, and dissecting them with proteomic techniques. Our approach is two-pronged: 1) to study signal transduction pathways initiated by NGF, and 2) to study mechanisms of apoptosis; with both prongs driving towards the same central question: what signalling mechanisms turn on or off the machinery that governs triggering of apoptosis? The emerging picture is that of a battle of signalling pathways vying for the life or death of the cell. The life forces are represented by pathways initiated by NGF binding to its receptor tyrosine kinase, TrkA, and the death forces by the cell death proteases, the caspase cascade that is initiated by release of cytochrome c (and other things) from mitochondria. The battleground is not simply individual proteins swimming in cytosol; battle tactics appear to involve small organelles (vesicles, particles), lipid rafts, mitochondria, and microtubules.

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SELECTED PUBLICATIONS

MacCormick, M. Moderscheim, T., van der Salm, L.W.M., Moore, A., Clements, S., McCaffrey, G., and Grimes, M.L. (2005). Distinct signalling particles containing Erk/Mek and B-Raf in PC12 cells. Biochemical J, 387:155-164.

Weible, M.W., Ozsarac, N., Grimes, M.L., and Hendry, I.A. (2004). Comparison of nerve terminal events in vivo effecting retrograde transport of vesicles containing neurotrophins or synaptic vesicle components. J Neurosci Res 750:771-781.

Grimes, M.L., and Miettinen, H. (2003). Receptor tyrosine kinase and G-protein coupled receptor signalling and sorting within endosomes. J Neurochem, 84: 905-918.

François, F. Godinho, M., Dragunow, M., and Grimes, M. (2001). A population of PC12 cells that is initiating apoptosis can be rescued by nerve growth factor, Mol. Cell. Neurosci., 18 :347-362.

François F, Godinho, MJ, and Grimes ML. (2000). Creb is cleaved by caspases in neural cell apoptosis. FEBS Lett, 486 : 281-284.